High-density lipoprotein (HDL) is the smallest, most dense lipoprotein in plasma. Epidemiological studies from the past four decades have consistently found that HDL levels are inversely correlated with the incidence of cardiovascular disease. The protective effect of HDL is largely attributed to either its role in reverse cholesterl transport or its anti-inflammatory property. The anti-inflammatory property was described in 1995, based on HDL's ability to block TNF-a-induced expression of the cellular adhesion molecules VCAM-1 and ICAM-1 in endothelial cells. Although numerous studies have confirmed this finding, the mechanism underlying this anti-inflammatory property remains unknown. I propose to focus on a new candidate for mediating HDL's anti-inflammatory property. Progranulin is a secreted growth factor that is expressed in many tissues and circulates in the blood. The progranulin gene, GRN, is mutated in some cases of familial frontotemporal dementia. Progranulin has been reported to be associated with HDL. Interestingly, recent studies revealed that progranulin binds to TNF receptors, thereby establishing a link between progranulin and inflammation. Specifically, current models posit that progranulin antagonizes TNF signaling by competing with TNF-a for binding to TNF receptors. Further, mice lacking progranulin have enhanced susceptibility to collagen-induced arthritis, illustrating functional consequences involving inflammation. This raises the intriguing hypothesis that progranulin significantly contributes to the anti-inflammatory property of HDL. Completion of these studies is expected to provide important insights into the molecular basis underlying HDL's anti-inflammatory property. Knowledge gleaned from these studies will likely have therapeutic implications for the prevention and treatment of cardiovascular disease. Moreover, it would be directly relevant to individuals with mutations in the GRN gene, which is mutated in some cases of frontotemporal dementia. PUBLIC HEALTH RELEVANCE: In this proposal, I will test the role of progranulin in mediating the anti-inflammatory property of HDL cholesterol, which is one mechanism by which HDL is thought to protect against cardiovascular disease. I will also determine the functional importance of progranulin using a mouse model of atherosclerosis. Completion of these studies is expected to provide important insights about the molecular basis underlying HDL's anti-inflammatory property, which would likely have therapeutic implications for the prevention and treatment of cardiovascular disease.